Sampling System

ABSTRACT

A sampling system comprises a mailing package; a cell sampling device comprising a flexible shaft having a handle at one end, wherein the shaft is configured to allow an individual to self collect a cell sample from mucous tissue, and a sample collecting element removably connectable with the other end of the shaft and operable to collect a cell sample from mucous tissue of an individual; and a sealable unit, wherein the unit is configured to store the sample collecting element having a cell sample thereon and to be received within the mailing package in its sealed form. The system may optionally further include a transport package configured to receive the remaining components of the system for delivery to a user.

FIELD OF THE INVENTION

The present invention relates generally to the field of screening andhealth control. More specifically the invention relates to a novelsampling system and associated methods suitable, for example, in testingto detect virus-associated cervical cancer, microbial infections andpathological changes.

BACKGROUND OF THE INVENTION

Cervical cancer is the second most common form of cancer in womenworld-wide. Invasive cervical carcinoma develops by progression of lesssevere epithelial changes, known as dysplacia and cervicalintraepithelial neoplacia (CIN I-II-III), into cervical carcinomas insitu (CIS).

Using vaginal aspirates (Pap smears), the epithelial changes can bedetected and classified by common cytological methods. It isparticularly important to notice that invasive cervical carcinoma ispreceded by its dysplastic precursor lesions, which can be present formonths or years before cervical carcinoma develops. Furthermore,progression to carcinoma can effectively be stopped by a simpleoperation (conization) if the precursor lesions are detected.

Many developed countries have experienced up to a 50% reduction in theincidence of and mortality from invasive cervical carcinoma after theintroduction of organized screening programs. Despite this fact, about500,000 women in the world are struck by cervical cancer each year. Inthe U.S., close to 5,000 women die each year from this disease. Thisnumber would drop further if more women were tested on a regular basis.

Of those who die of cervical cancer, 50% have not had a Pap test done in5 or more years. Indeed, those women who do not participate in thegynecological health control and those who show false negative cytologyare the highest risk groups for cervical cancer. The efficacy andreliability of the sampling method and the sample's analysis aretherefore primary issues. This involves, in the first place, reachingthose women who do not now participate in the gynecological screening byproviding a simple and reliable device for sampling, and secondly, toincrease the discriminating efficacy of the analytical methods todiagnose infections, precancerous lesions or cancerous lesions.

Association between papillomavirus (HPV) infection and cervicalcarcinoma was postulated in the 1970's. The International BiologicalStudy on Cervical Cancer reported a world-wide prevalence of infectionwith HPV of 93% in women with invasive cervical cancer. In addition, thesubtypes HPV 16 and HPV 18 are the most significant risk factors in itsaetiology. HPV infection is also an important risk factor forprogression of CIN.

Recent studies with improved methods of polymerase chain reaction (PCR)imply an overall HPV prevalence of almost 100% and that the PCR resultscorrelate with the histological findings. These results reinforce therational for HPV testing in combination with, or even instead of,cytology in population-based screening programs.

Determination of squamous intraepithelial lesions, or cervicaldysplacia, is commonly used as an indication of progression to cervicalcancer. Alternatively, the presence of HPV nucleic acid in a patientsample, following amplification by PCR, is taken as a risk factor forprogression to cervical cancer. From the above, it is obvious thatcytology and PCR analysis of HPV infection provide very efficient meansto detect individuals at risk to develop cervical cancer.

Recently published evidence-based consensus guidelines for themanagement of women with cervical cytological abnormalities and cervicalcancer precursors state that women with atypical squamous cells ofundetermined significance (ASCUS) should be managed using a program of 2repeat cytology tests, immediate colposcopy, or DNA testing forhigh-risk types of HPV. Testing for HPV DNA is the preferred approachwhen liquid-based cytology is used for screening.

The limiting factor in order to further decrease the incidence of andmortality from cervical cancer appears therefore to be related toreaching the non attending women and providing a simple sampling devicegiving relevant samples for HPV analysis and/or cytology.

Traditionally, sampling of vaginal smear requires scraping of a woman'scervix with a sampling device, such as a spatula or a brush. Thissampling is generally performed by medical professionals likegynecologists, midwifes or nurses in a clinical environment. Many women,who now refrain from such gynecological testing, would participate ifthe sampling could be carried out at home and/or by the womenthemselves. Self and home sampling would therefore increase theparticipation in the gynecological screening, and by that means,decrease the incidence of cervical cancer.

In addition to the above, sampling systems are also in demand for DNAanalysis. Law enforcement officials, paternity agents, etc. areconstantly taking DNA samples to help solve crimes, determine paternity,etc. As the results of the tests done on these samples dramaticallyaffect people's lives and may be desired as evidence in legalproceedings, the sampling must be done in a manner in which the samplecontamination is reduced or avoided. As such, there is a need for animproved sampling system.

SUMMARY OF THE INVENTION

In view of the need for an improved sampling device and a system easilyadaptable to present health screening procedures, the present inventiontherefore provides improvement over the currently available devices andsystems.

In one embodiment, the present invention comprises a sampling systemcomprising: a) a mailing package; b) a cell sampling device comprising:i) a flexible shaft having a handle at one end, wherein the shaft isconfigured to allow an individual to self collect a cell sample frommucous tissue, and ii) a sample collecting element removably connectablewith the other end of the shaft and operable to collect a cell samplefrom mucous tissue of an individual; and c) a sealable unit, wherein theunit is configured to store the sample collecting element having a cellsample thereon and to be received within the mailing package in itssealed form. The sampling system may optionally further include atransport package configured to receive components a)-c) for delivery toa user.

In another embodiment, the present invention comprises a sampling systemcomprising: a) a mailing package; b) an instruction sheet; c) a flexibleshaft; d) a sample collecting element connected with an end of the shaftand having a plurality of raised portions and grooves; e) a bar codedunit including an air tight cover and configured to receive the samplecollecting element therein and to be received in the mailing package;and f) a bar-coded transport package configured to receive componentsa)-e) for delivery to a user.

The sampling systems of the invention may be used by medical personnelfor patient sampling and/or may be used by individuals forself-sampling. The sampling systems are particularly advantageous foruse by an individual in conduct self-sampling in testing to detect, forexample, virus-associated cervical cancer, microbial infections andpathological changes. These and additional embodiments and advantagesmay be more fully apparent in view of the detailed description.

BRIEF DESCRIPTION OF THE DRAWINGS

The present invention will be more fully understood from the detaileddescription, given herein below and the accompanying drawings which aregiven for illustration, and thus not limiting the scope of theinvention, and wherein

FIGS. 1A and 1B are, respectively, a front view of mailing package and arear view of a bar-coded transport package included in one embodiment ofthe sampling system according to the invention;

FIG. 2 is a top view of a sampling device and a sealable unit held in aprotective plastic tray, in accordance with one embodiment of thesampling system of the invention;

FIGS. 3A-3J show schematic plan and cross-sectional views of a samplingdevice included in one embodiment of a sampling system according to theinvention; and

FIG. 4 is an illustration of an instruction sheet suitable for use inaccordance with one embodiment of the sampling system of the invention.

The embodiments set forth in the drawings are illustrative in nature andare not intended to be limiting of the invention defined by the claims.Moreover, individual features of the drawings and the invention will bemore fully apparent and understood in view of the following detaileddescription.

DETAILED DESCRIPTION

The present invention provides a sampling system that overcomesdisadvantages of prior art devices, instruments and procedures forobtaining cell samples from mucous tissue such as, but not limited to,the gynecological tract and the mouth.

In a first aspect, the present invention provides a sampling systemwhich may be employed by an individual to easily and reliably, at homeor at a visit to a medical location, under hygienic conditions, takecell smears and samples, for example, gynecological samples, from mucoustissues. The samples can be transported without risk of contamination ortransmission of infective agents, and thereafter be analyzed by chemicalmethods, such as PCR, or by other microbiological methods.

With reference to FIGS. 1-4, the sampling system according to oneembodiment of the present invention includes a cell sampling device 2for taking cell samples, a mailing package 14 for returning a sample to,for example, a laboratory for testing, and a sealable unit 7.Optionally, the sampling system may include a transport package 3 fordelivery of the sampling system components to a user. One embodiment ofthe transport package 3 is shown in FIG. 1B, and includes a bar code,for use as described in further detail below. One embodiment of themailing package 14, including a printed address for mailing a sample tothe appropriate medical professional, on the front side thereof is shownin FIG. 1A. It will be appreciated that the transport package 3 and themailing package 14 may be provided with this exemplary information, orother information as desired, in any suitable arrangement. The mailingpackage 14 allows return of the sealable unit 7 and contents thereof tothe appropriate facility, for example, by mail, courier or the like,without compromising the sealable unit or its contents.

In one embodiment, the cell sampling device 2 comprises a shaft 4 havinga handle 5 at one end. The handle may include a lower lip 5 a as shownto facilitate the ease of use of the device. The shaft 4 is configuredto allow an individual to self collect a cell sample from mucous tissue.In a specific embodiment, the shaft 4 is configured to allow anindividual to self collect a sample from a cervix location. In anadditional embodiment, at least a portion of the shaft is flexible, andin a further embodiment, a portion of the shaft 4 is rigid.Alternatively, the shaft may be entirely flexible. Reference to aflexible shaft is intended to mean at least a portion of the shaft isflexible. In another embodiment, the shaft 4 is formed of a polymer,including, for example, polypropylene, polyethylene, or a mixturethereof.

The cell sampling device 2 further comprises a sample collecting element6 removably connectable with the other end of the shaft 4 opposite thehandle. The element 6 is operable to collect a cell sample from mucoustissue of an individual. FIGS. 3A and 3B show the sample collectingelement 6 removable connected with the shaft 4, while FIGS. 3C and 3Eshow the shaft 4 without the sample collecting element 6 thereon andFIGS. 3H and 3I show the sample collecting element 6 apart from theshaft 4. FIG. 3D shows a cross-sectional view taken along line D-D inFIG. 3C; FIGS. 3F and 3G show cross-sectional views taken along linesF-F and G-G in FIG. 3E, respectively, and FIG. 3J shows across-sectional view taking along line J-J in FIG. 3I.

The sealable unit 7 is configured to store the sample collection element6 having a cell sample thereon, preferably in a manner which preventscontamination of the element 6, i.e., in an air tight manner, and to bereceived within the mailing package 14 in its sealed form. In onespecific embodiment, the unit 7 is a sealable tube.

In an additional embodiment, the transport package 3 and the unit 7 eachhave an identification element 8, for example correlating to theindividual from which a sample is made. In a further embodiment, theidentification element 8 consists of a bar code.

The shaft 4, the adsorbing sample collecting element 6, the sealableunit 7, and the unit cover 12 can be manufactured of any suitablematerials as desired. For example, these components may be formed of thesame or different plastic materials. In a further embodiment, a plasticmaterial of the cell sampling device 2, preferentially polypropylene, isselected with a flexural modulus giving the shaft 4 flexibility tofollow the anatomy of the vagina to reach portio vaginalis and at thesame time rigid enough to get a close contact between the samplecollecting element 6 and the mucous tissue ectocervix.

In a specific embodiment as shown in FIGS. 3A, 3B and 3H-3J, the samplecollecting element 6 is generally cylindrical. The element 6 may beconfigured and sized as desired for a particular sample collection. Inone embodiment, the element 6 is generally cylindrical as shown and hasa diameter from about 2 to about 20 mm. In one embodiment as shown inFIGS. 3A, 3B, 3H and 3I, the front part of the sample collecting element6 is rounded and may be made very smooth, so as to render it more tissuefriendly and easier for introduction into the sensitive tissue of thevagina.

In a further embodiment, the sample collecting element 6 comprises atleast one raised portion 9. In another embodiment, the raised portionsof the sample collecting element 6 form a plurality of cell and mucousadsorbing segments 10. The segments 10 are separated by at least onegroove 11 or a plurality of grooves 11. In a specific embodiment, thegrooves 11 are from about 0.01 to 2 mm in width and in anotherembodiment, the raised portions 9 include an edge at the groove 11capable of scraping tissue to collect a sample. In an additionalembodiment, the raised portions 9 forming the segments 10 and thegrooves 11 are configured to collect a cell sample and hold the samplewithin the grooves 11 even during withdrawal of the device 2 from a bodyorifice. In a specific embodiment, the segments 10 of the samplecollecting element 6 have an unpolished surface and, in a specificembodiment, comprise an abrasive surface, for example having a surfaceroughness of about 1 to 100 μm, to facilitate release of cell-containingmucous, for example, from ectocervix tissue.

In one embodiment, the raised portions 9 form segments 10 which areessentially rectangular in shape by providing the grooves 11 in thelongitudinal and transversal directions on the sample collecting element6. However, it is of course possible to provide grooves 11 in othergeometries, e.g. in spiral or zigzag patterns. In one embodiment, thegrooves 11 are substantially narrower than the width of the raisedportions 9. In one embodiment the width of the grooves 11 does notexceed about 2 mm, and in another embodiment, the width is from about0.5 to about 0.1 mm. Importantly, the grooves 11 should be able toabsorb mucous liquid and cells therein, and maintain these materials inplace during retraction of the device from the body orifice.

The sample collecting element 6 is removably connected with one end ofthe shaft 4. Thus, the sample collecting element 6 may be connected withthe shaft to facilitate obtaining a mucous sample, for example fromectocervix tissue, and may then be removed from the shaft 4 forinsertion in the sealable unit 7. One of ordinary skill in the art willappreciate that various connection configurations may be employed tofacilitate the removable connection of the sample collecting element 6with the end of the shaft 4. In the specific embodiments shown in FIG.3A-3J, an end of the sample collecting element 6 is provided with anextension 13 having protrusions 15. The end of the shaft 4 iscorrespondingly provided with extensions 16 having grooves adapted toreceive protrusions 15 therein in a snap-fit manner. Thus, the extension13 is inserted between the extensions 16 in a male-female type manner inwhich the protrusions 15 are snap fit within grooves contained in theextension 16 at the end of the shaft 4. The protrusions are releasedfrom the grooves contained in extension 16 by rotation of the samplecollecting element 6 as shown in FIG. 3B. As a result, the samplecollecting element 6 may be removed from the shaft 4 to the unit 7 andpreferably sealed therein, for example with a unit cover 12 as shown inFIG. 2. Advantageously, to prevent contamination of the samplecollecting element 6 once a mucous sample is adhered thereto, the samplecollecting element may be at least partially inserted within the unit 7,prior to removal of the sample collecting element 6 from the shaft 4.The unit 7 may then be moved to rotate the sample collecting element asshown in FIG. 3B and release the sample collecting element fromextension 16 of the shaft 4. After release of the sample collectingelement from its connection with the shaft 4, the remainder of thesample collecting element is then inserted into the unit 7, for exampleby gravity by holding the sample collection unit an upright verticalposition, or by pushing the sample collected element further into theunit with the end of the shaft 4. The unit is then sealed with theappropriate cover, preferably to form an airtight seal.

The sealed unit 7, having the sample collecting element 6 therein, maythen be placed in the mailing package 14 which is designed to protectthe sealed unit during return transport of the sealed unit to a medicalfacility, for example a doctor's office, hospital or laboratory, forappropriate testing of the collected sample therein.

In one embodiment, the sample collecting system further comprises aninstruction sheet 20, particularly useful when the sampling system isadapted for self sampling by an individual.

In one embodiment, the sampling system of the invention is configured toallow an individual to self-collect a sample. In an additionalembodiment, the self-sampling device is configured to allow anindividual to collect a sample from mucous tissue. In anotherembodiment, the mucous tissue resides in the gynecological tract and inanother embodiment the mucous tissue resides in the mouth, (e.g. cheek).The sampling system may be used by distribution to a patient, whoconducts sampling and returns the sample for final laboratory analysisaccording to the present invention.

EXAMPLE

This example examines if the same result will be obtained whengynecological smears are taken by hospital staff using previous standardprocedures or using the sampling system according to the presentinvention, as well as if patients themselves use the sampling system.

Thirty six women are requested to come to the hospital for regulargynecological control and participate in the study. The hospital staffsecure gynecological smears from the portio area with the use of acytobrush. One sample is used for conventional cytological screening andthe other for HPV analysis. The women take one sample themselves withthe present invention following the written information as shown in FIG.4. This sample is used for HPV analysis.

All samples are sent to the Department of Pathology, University ofUppsala. The smears collected with cytobrush by the gynecological staffand the smears collected by the women themselves with the device areanalyzed for presence of HPV with the Hybrid Capture II method (DigeneDiagnostics Inc., Silver Spring, Md., USA). The cytological smears are,after screening, examined for HPV using a PCR based technique.

All samples taken with previous standard procedures are scraped intotest tubes and PCR buffer and proteinase K is added. When samples aretaken with the device according to the present invention, the PCR bufferand proteinase K are simply added into the sealable unit, either by theuser, or prior to delivery of the sampling system to a user, or uponreturn of the unit to, for example, a testing facility. The cells aredigested at 60° C. and the DNA fraction recovered with standard methods.

The PCR amplification is performed in 100 μl volume containing standardamplification reagents. Type-specific PCR amplification is performedunder conditions described by Brule et al. using GP5+/GP6+ generalprimers. Samples with HPV DNA amplicones are sequenced with an ABI PRISM310 Genetic Analyzer (Applied Biosystems, Foster City, Calif.) afterwhich the HPV type can be determined.

The results from these studies demonstrate that the women themselves canreadily secure gynecological samples with the device according to thepresent invention. Furthermore, both cytological and PCR analysis of thesamples give essentially the same result as when medical staff take thesamples either using the present device or other previously wellestablished sampling methods. It is demonstrated that the analysis canbe carried out with satisfactory results three days after sampling withthe device.

Thus, the sampling system is particularly advantageous for self-samplingfor gynecological samples, and particularly HPV analysis. After selfsampling at home, the device may be rapidly returned by mail to ahospital laboratory for HPV analysis. The sampling system according tothe present invention is surprisingly well accepted, and is particularlyuseful for self sampling at home.

The sampling system will increase participation in the gynecologicalscreening programs evaluating the risk of developing cervical cancer insitu. Self and home sampling will be positive from a health-economicpoint of view, but more importantly, increased participation willdecrease the incidence of cervical cancer and also decrease the numberof women who die of this disease.

The specific illustrations and embodiments described herein areexemplary only in nature and are not intended to be limiting of theinvention defined by the claims. Further embodiments and examples willbe apparent to one of ordinary skill in the art in view of thisspecification and are within the scope of the claimed invention.

1. A sampling system comprising: a) a mailing package; b) a cellsampling device comprising: i) a flexible shaft having a handle at oneend, wherein the shaft is configured to allow an individual to selfcollect a cell sample from mucous tissue, and ii) a sample collectingelement removably connectable with the other end of the shaft andoperable to collect a cell sample from mucous tissue of an individual;and c) a sealable unit, wherein the unit is configured to store thesample collecting element having a cell sample thereon and to bereceived within the mailing package in its sealed form.
 2. The system ofclaim 1, wherein the shaft is configured to allow an individual to selfcollect a cell sample from a cervix location.
 3. The system of claim 1,further comprising a transport package configured to receive componentsa)-c) for delivery to an individual for use of the system.
 4. The systemof claim 3, wherein the transport package and the unit each have anidentification element.
 5. The system of claim 4, wherein theidentification element includes a bar code.
 6. The system of claim 1,wherein a portion of the shaft is rigid.
 7. The system of claim 1,wherein the shaft is formed of polymer comprising polypropylene,polyethylene, or a mixture thereof.
 8. The system of claim 1, whereinthe sample collecting element is generally cylindrical and has adiameter of from about 2 to about 20 mm.
 9. The system of claim 1,wherein the sample collecting element comprises at least one raisedportion.
 10. The system of claim 1, wherein the raised portion forms aplurality of cell and mucous collecting segments.
 11. The system ofclaim 10, wherein the sample collecting element further comprises atleast one groove which is from about 0.01 to about 2 mm in width formaintaining a cell and mucous sample therein.
 12. The system of claim11, wherein the raised portion forms an edge at the groove capable ofscraping tissue to collect a sample.
 13. The system of claim 12, whereinthe raised portion and grooves are configured to collect a sample byinsertion in a body orifice and to hold a collected sample duringwithdrawal of the device from a body orifice.
 14. The system of claim 1,wherein the sample collecting element comprises an abrasive surface. 15.The system of claim 14, wherein the abrasive surface has a surfaceroughness of from about 1 to about 100 μm.
 16. The system of claim 1,wherein the sealable unit comprise a unit cover for sealing the unit.17. The system of claim 1, wherein the sample collecting element, theshaft and the sealable unit are configured to allow the samplecollecting element to be at least partially inserted within the sealableunit and separated from the shaft without contact of the samplecollecting element by an individual.
 18. The system of claim 17, whereinthe connection comprises a snap-fit mechanism.
 19. The system of claim16, wherein the unit and the unit cover form an air-tight seal.
 20. Thesystem of claim 1, further comprising an instruction sheet.
 21. Asampling system comprising: a) a preaddressed mailing package; b) aninstruction sheet; c) a flexible shaft; d) a sample collecting elementremovably connectable with an end of the shaft and having a plurality ofraised portions and grooves; e) a bar coded unit including an air tightunit cover and configured to receive the sample collecting elementtherein and to be received in the mailing package; and f) a transportpackage configured to receive components a)-e) for delivery to a user.22. The sampling system of claim 21, wherein the sample collectingelement is configured for snap-fit connection and removal with theshaft.
 23. The sampling system of claim 22, wherein the cell samplingdevice is configured to allow an individual to self collect a sample.24. The sampling system of claim 23, wherein the cell sampling device isconfigured to allow an individual to collect a sample from mucoustissue.
 25. The sampling system of claim 24, wherein the mucous tissueresides in the gynecological tract.
 26. The sampling system of claim 24,wherein the mucous tissue resides in the mouth.